Colorectal Cancer Diagnosis: The Obstacles We Face in Determining a Non-Invasive Test and Current Advances in Biomarker Detection

Abstract

Globally, colorectal cancer (CRC) is the third most common cancer, with 1.4 million new cases and over 700,000 deaths per annum. Despite being one of the most common cancers, few molecular approaches to detect CRC exist. Carcinoembryonic antigen (CEA) is a known serum biomarker that is used in CRC for monitoring disease recurrence or response to treatment. However, it can also be raised in multiple benign conditions, thus having no value in early detection or screening for CRC. Molecular biomarkers play an ever-increasing role in the diagnosis, prognosis, and outcome prediction of disease, however, only a limited number of biomarkers are available and none are suitable for early detection and screening of CRC. A PCR-based Epi proColon^® blood plasma test for the detection of methylated SEPT9 has been approved by the USFDA for CRC screening in the USA, alongside a stool test for methylated DNA from CRC cells. However, these are reserved for patients who decline traditional screening methods. There remains an urgent need for the development of non-invasive molecular biomarkers that are highly specific and sensitive to CRC and that can be used routinely for early detection and screening. A molecular approach to the discovery of CRC biomarkers focuses on the analysis of the transcriptome of cancer cells to identify differentially expressed genes and proteins. A systematic search of the literature yielded over 100 differentially expressed CRC molecular markers, of which the vast majority are overexpressed in CRC. In terms of function, they largely belong to biological pathways involved in cell division, regulation of gene expression, or cell proliferation, to name a few. This review evaluates the current methods used for CRC screening, current availability of biomarkers, and new advances within the field of biomarker detection for screening and early diagnosis of CRC.

Keywords: biomarkers; cancer detection; cancer screening; cancer treatment; colorectal cancer.

Figure 1

Bowel cancer survival by stage of disease at diagnosis. Solid blue and red lines denote one-year survival post-diagnosis for males and females, respectively. Open circles show survival rates (%) for males and females (blue and red, respectively) where no staging data are available. Dotted lines indicate five-year net survival. Numbers of cases are shown as blue bars (males) and pink bars (females)—right vertical axis. Horizontal axis—stage at diagnosis. Data are from [9] and refer to adults diagnosed in 2013–2017 and followed up to 2018.

Figure 2

Wnt signaling pathway. Three pathways are shown—canonical, planar cell polarity (PCP), and Wnt/Ca²⁺. Molecules, pathways, and interactions implicated in CRC are highlighted. Reproduced from [44] with permission.

Figure 3

Colorectal cancer pathways. Molecules, pathways, and interactions implicated in CRC are highlighted. Reproduced from [49] with permission.

Figure 4

Summary of the main results of a study comparing FIT stool test to methylated DNA stool test for the detection of colorectal cancer [84].